Severe combined immunodeficiencies (SCID) are a heterogeneous group of fatal inherited disorders characterized by a profound reduction or absence of T lymphocyte function. The most common form of SCID is an X-linked form (SCID-X1) caused by defects in the common cytokine receptor ? chain (?c or IL-2RG). Until the recent advent of somatic gene therapy, hematopoietic stem cell transplantation (HSCT) offered the only curative option for patients with any form of SCID. In the 20-25% of cases when a genotypically matched sibling donor is available, HSCT is a highly successful procedure. For the remaining individuals, alternative donor transplants, principally from matched unrelated (MUD) or haploidentical parental donors have been problematic due to toxicity from ablative therapy, graft-versus-host disease and incomplete lymphoid reconstitution. Recent gene transfer trials have documented efficacy, albeit with toxicity related to insertional mutagenesis. We have developed a next generation self-inactivating (SIN) vector expressing the IL-2RG gene controlled by an internal cellular promoter, pSRS11.EFS.IL2RG.pre* and have shown this vector to have reduced mutagenic potential compared to LTR configuration in non-clinical studies. We hypothesize that this vector will have similar efficacy to the vector used in the past trial but without insertional mutagenesis. The current study is a phase l/ll trial of somatic gene therapy for patients with SCID-X1. Inclusion criteria include patients with a definitive diagnosis of SCIDX1 in whom HLA-matched family donors are unavailable and who are either patients >3.5 months old and lack an HLA identical (A,B,C,DR,DQ) unrelated donor OR patients of any age with an active, therapy-resistant infection or other medical conditions that significantly increase the risk of allogeneic transplant. Primary endpoints include immunological reconstitution defined as absolute CD3 cells of >300/l and PHA stimulation index >15 at 6 months post infusion and the incidence of life-threatening adverse reactions related to the gene transfer procedure. We will also perform detailed immune reconstitution and insertion site analysis studies.